Post-Ablation cardiac Magnetic resonance to assess Ventricular Tachycardia recurrence (PAM-VT study).

AIMS: Conducting channels (CCs) detected by late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) are related to ventricular tachycardia (VT). The aim of this work was to study the ability of post-ablation LGE-CMR to evaluate ablation lesions. METHODS AND RESULTS: This is a prospective study of consecutive patients referred for a scar-related VT ablation. LGE-CMR was performed 6-12 months prior to ablation and 3-6 months after ablation. Scar characteristics of pre- and post-ablation LGE-CMR were compared. During the study period (March 2019-April 2021), 61 consecutive patients underwent scar-related VT ablation after LGE-CMR. Overall, 12 patients were excluded (4 had poor-quality LGE-CMR, 2 died before post-ablation LGE-CMR, and 6 underwent post-ablation LGE-CMR 12 months after ablation). Finally, 49 patients (age: 65.5 ± 9.8 years, 97.9% male, left ventricular ejection fraction: 34.8 ± 10.4%, 87.7% ischaemic cardiomyopathy) were included. Post-ablation LGE-CMR showed a decrease in the number (3.34 ± 1.03 vs. 1.6 ± 0.2; P < 0.0001) and mass (8.45 ± 1.3 vs. 3.5 ± 0.6 g; P < 0.001) of CCs. Arrhythmogenic CCs disappeared in 74.4% of patients. Dark core was detected in 75.5% of patients, and its presence was not related to CC reduction (52.2 ± 7.4% vs. 40.8 ± 10.6%, P = 0.57). VT recurrence after one year follow-up was 16.3%. The presence of two or more channels in the post-ablation LGE-CMR was a predictor of VT recurrence (31.82% vs. 0%, P = 0.0038) with a sensibility of 100% and specificity of 61% (area under the curve 0.82). In the same line, a reduction of CCs < 55% had sensibility of 100% and specificity of 61% (area under the curve 0.83) to predict VT recurrence. CONCLUSION: Post-ablation LGE-CMR is feasible, and a reduction in the number of CCs is related with lower risk of VT recurrence. The dark core was not present in all patients. A decrease in VT substrate was also observed in patients without a dark core area in the post-ablation LGE-CMR.

Arrhythmogenic Right Ventricular Cardiomyopathy With Extensive Abnormal Substrate: Is Isolation Possible?

BACKGROUND: In arrhythmogenic right ventricular cardiomyopathy (ARVC) patients with extensive right ventricular free wall (RVFW) abnormal substrate, large-area homogenization with combined epicardial and endocardial approach is time consuming and often inadequate for modification. OBJECTIVES: This study aimed to explore the feasibility and efficacy of RVFW abnormal substrate isolation in such patients to control ventricular tachycardia (VT). METHODS: Eight consecutive ARVC patients with VT who had extensive abnormal RVFW substrate were included. VT induction was performed before substrate mapping and modification. Detailed voltage mapping was done during sinus rhythm. A circumferential linear lesion was deployed along the border zone of low-voltage area on the RVFW to achieve electrical isolation. Other small areas with fractionated or late potentials were further homogenized. RESULTS: All 8 patients had RVFW endocardial low-voltage area. The entire RV low-voltage area was 113.8 ± 84.1 cm2 (49.6% ± 29.8%) and the dense scar was 59.6 ± 39.8 cm2 (25.0% ± 14.1%). Electrical isolation of abnormal substrate was achieved in 5 of 8 (62.5%) patients via endocardial approach alone and 3 of 8 (37.5%) patients via a combination of endocardial and epicardial approach. Electrical isolation was verified by slow automaticity (5 of 8, 62.5%) or RV noncapture (3 of 8, 37.5%) during high-output pacing inside the encircled area. VTs were induced in 6 patients before ablation, and all patients were rendered noninducible after ablation. During a median follow-up of 43 months (range: 24-53 months), 7 of 8 (87.5%) patients remained free of sustained VT. CONCLUSIONS: Electrical isolation of RVFW is feasible and can be the option in ARVC patients with extensive abnormal substrate.

Left Ventricular Hypertrophy and Ventricular Tachyarrhythmia: The Role of Biomarkers.

Left ventricular hypertrophy (LVH) refers to a complex rebuilding of the left ventricle that can gradually lead to serious complications-heart failure and life-threatening ventricular arrhythmias. LVH is defined as an increase in the size of the left ventricle (i.e., anatomically), therefore the basic diagnosis detecting the increase in the LV size is the domain of imaging methods such as echocardiography and cardiac magnetic resonance. However, to evaluate the functional status indicating the gradual deterioration of the left ventricular myocardium, additional methods are available approaching the complex process of hypertrophic remodeling. The novel molecular and genetic biomarkers provide insights on the underlying processes, representing a potential basis for targeted therapy. This review summarizes the spectrum of the main biomarkers employed in the LVH valuation.

Genetic Inhibition of Mitochondrial Permeability Transition Pore Exacerbates Ryanodine Receptor 2 Dysfunction in Arrhythmic Disease.

The brief opening mode of the mitochondrial permeability transition pore (mPTP) serves as a calcium (Ca2+) release valve to prevent mitochondrial Ca2+ (mCa2+) overload. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced arrhythmic syndrome due to mutations in the Ca2+ release channel complex of ryanodine receptor 2 (RyR2). We hypothesize that inhibiting the mPTP opening in CPVT exacerbates the disease phenotype. By crossbreeding a CPVT model of CASQ2 knockout (KO) with a mouse missing CypD, an activator of mPTP, a double KO model (DKO) was generated. Echocardiography, cardiac histology, and live-cell imaging were employed to assess the severity of cardiac pathology. Western blot and RNAseq were performed to evaluate the contribution of various signaling pathways. Although exacerbated arrhythmias were reported, the DKO model did not exhibit pathological remodeling. Myocyte Ca2+ handling was similar to that of the CASQ2 KO mouse at a low pacing frequency. However, increased ROS production, activation of the CaMKII pathway, and hyperphosphorylation of RyR2 were detected in DKO. Transcriptome analysis identified altered gene expression profiles associated with electrical instability in DKO. Our study provides evidence that genetic inhibition of mPTP exacerbates RyR2 dysfunction in CPVT by increasing activation of the CaMKII pathway and subsequent hyperphosphorylation of RyR2.

Role of Ca2+ in healthy and pathologic cardiac function: from normal excitation-contraction coupling to mutations that cause inherited arrhythmia.

Calcium (Ca2+) ions are a key second messenger involved in the rhythmic excitation and contraction of cardiomyocytes throughout the heart. Proper function of Ca2+-handling proteins is required for healthy cardiac function, whereas disruption in any of these can cause cardiac arrhythmias. This comprehensive review provides a broad overview of the roles of Ca2+-handling proteins and their regulators in healthy cardiac function and the mechanisms by which mutations in these proteins contribute to inherited arrhythmias. Major Ca2+ channels and Ca2+-sensitive regulatory proteins involved in cardiac excitation-contraction coupling are discussed, with special emphasis on the function of the RyR2 macromolecular complex. Inherited arrhythmia disorders including catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, Brugada syndrome, short QT syndrome, and arrhythmogenic right-ventricular cardiomyopathy are discussed with particular emphasis on subtypes caused by mutations in Ca2+-handling proteins.

Effects of Cardiac Stem Cell on Postinfarction Arrhythmogenic Substrate.

Clinical data suggest that cardiosphere-derived cells (CDCs) could modify post-infarction scar and ventricular remodeling and reduce the incidence of ventricular tachycardia (VT). This paper assesses the effect of CDCs on VT substrate in a pig model of postinfarction monomorphic VT. We studied the effect of CDCs on the electrophysiological properties and histological structure of dense scar and heterogeneous tissue (HT). Optical mapping and histological evaluation were performed 16 weeks after the induction of a myocardial infarction by transient occlusion of the left anterior descending (LAD) artery in 21 pigs. Four weeks after LAD occlusion, pigs were randomized to receive intracoronary plus trans-myocardial CDCs (IC+TM group, n: 10) or to a control group. Optical mapping (OM) showed an action potential duration (APD) gradient between HT and normal tissue in both groups. CDCs increased conduction velocity (53 ± 5 vs. 45 ± 6 cm/s, p < 0.01), prolonged APD (280 ± 30 ms vs. 220 ± 40 ms, p < 0.01) and decreased APD dispersion in the HT. During OM, a VT was induced in one and seven of the IC+TM and control hearts (p = 0.03), respectively; five of these VTs had their critical isthmus located in intra-scar HT found adjacent to the coronary arteries. Histological evaluation of HT revealed less fibrosis (p < 0.01), lower density of myofibroblasts (p = 0.001), and higher density of connexin-43 in the IC+TM group. Scar and left ventricular volumes did not show differences between groups. Allogeneic CDCs early after myocardial infarction can modify the structure and electrophysiology of post-infarction scar. These findings pave the way for novel therapeutic properties of CDCs.

Characterization of N-terminal RYR2 variants outside CPVT1 hotspot regions using patient iPSCs reveal pathogenesis and therapeutic potential.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a cardiac channelopathy causing ventricular tachycardia following adrenergic stimulation. Pathogenic variants in RYR2-encoded ryanodine receptor 2 (RYR2) cause CPVT1 and cluster into domains I-IV, with the most N-terminal domain involving residues 77-466. Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated for RYR2-F13L, -L14P, -R15P, and -R176Q variants. Isogenic control iPSCs were generated using CRISPR-Cas9/PiggyBac. Fluo-4 Ca2+ imaging assessed Ca2+ handling with/without isoproterenol (ISO), nadolol (Nad), and flecainide (Flec) treatment. CPVT1 iPSC-CMs displayed increased Ca2+ sparking and Ca2+ transient amplitude following ISO compared with control. Combined Nad treatment/ISO stimulation reduced Ca2+ amplitude and sparking in variant iPSC-CMs. Molecular dynamic simulations visualized the structural role of these variants. We provide the first functional evidence that these most proximal N-terminal localizing variants alter calcium handling similar to CPVT1. These variants are located at the N-terminal domain and the central domain interface and could destabilize the RYR2 channel promoting Ca2+ leak-triggered arrhythmias.

Predicting arrhythmia recurrence following catheter ablation for ventricular tachycardia using late gadolinium enhancement magnetic resonance imaging: Implications of varying scar ranges.

BACKGROUND: Thresholding-based analysis of late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) can create scar maps and identify corridors that might provide a reentrant substrate for ventricular tachycardia (VT). Current recommendations use a full-width-at-half-maximum approach, effectively classifying areas with a pixel signal intensity (PSI) >40% as border zone (BZ) and >60% as core. OBJECTIVE: The purpose of this study was to investigate the impact of 4 different threshold settings on scar and corridor quantification and to correlate this with postablation VT recurrence. METHODS: Twenty-seven patients with ischemic cardiomyopathy who had undergone catheter ablation for VT were included for retrospective analysis. LGE-CMR images were analyzed using ADAS3D LV. Scar maps were created for 4 PSI thresholds (40-60, 35-65, 30-70, and 45-55), and the extent of variation in BZ and core, as well as the number and weight of conduction corridors, were quantified. Three-dimensional representations were reconstructed from exported segmentations and used to quantify the surface area between healthy myocardium and scar (BZ + core), and between BZ and core. RESULTS: A wider PSI threshold was associated with an increase in BZ mass and decrease in scar (P <.001). No significant differences were observed for the total number of corridors and their mass with increasing PSI threshold. The best correlation in predicting arrhythmia recurrence was observed for PSI 45-55 (area under the curve 0.807; P = .001). CONCLUSION: Varying PSI has a significant impact on quantification of LGE-CMR parameters and may have incremental clinical value in predicting arrhythmia recurrence. Further prospective investigation is warranted to clarify the functional implications of these findings for LGE-CMR-guided ventricular ablation.

Generation of an induced pluripotent stem cell line from a Chinese Han child with catecholaminergic polymorphic ventricular tachycardia.

TECRL, first reported in a Sudanese family with catecholaminergic polymorphic ventricular tachycardia (CPVT) in 2016. TECRL, is an endoplasmic reticulum (ER) protein preferentially expressed in the heart, playing a role in cardiomyocyte calcium homeostasis. Using Sendaivirus-mediated reprogramming, we generated an induced pluripotent stem cell (iPSC) line from the CPVT patient's peripheral blood mononuclear cell. The iPSC exhibited stable amplification, expressed pluripotent markers, and differentiated spontaneously into three layers in vitro. Additionally, the iPSC line maintained a normal karyotype, retained the pathogenic TECRL mutation, and the cell resource facilitated a platform to explore the CPVT mechanisms related to TECRL mutations.

TECRL deficiency results in aberrant mitochondrial function in cardiomyocytes.

Sudden cardiac death (SCD) caused by ventricular arrhythmias is the leading cause of mortality of cardiovascular disease. Mutation in TECRL, an endoplasmic reticulum protein, was first reported in catecholaminergic polymorphic ventricular tachycardia during which a patient succumbed to SCD. Using loss- and gain-of-function approaches, we investigated the role of TECRL in murine and human cardiomyocytes. Tecrl (knockout, KO) mouse shows significantly aggravated cardiac dysfunction, evidenced by the decrease of ejection fraction and fractional shortening. Mechanistically, TECRL deficiency impairs mitochondrial respiration, which is characterized by reduced adenosine triphosphate production, increased fatty acid synthase (FAS) and reactive oxygen species production, along with decreased MFN2, p-AKT (Ser473), and NRF2 expressions. Overexpression of TECRL induces mitochondrial respiration, in PI3K/AKT dependent manner. TECRL regulates mitochondrial function mainly through PI3K/AKT signaling and the mitochondrial fusion protein MFN2. Apoptosis inducing factor (AIF) and cytochrome C (Cyc) is released from the mitochondria into the cytoplasm after siTECRL infection, as demonstrated by immunofluorescent staining and western blotting. Herein, we propose a previously unrecognized TECRL mechanism in regulating CPVT and may provide possible support for therapeutic target in CPVT.

On the Electrophysiology and Mapping of Intramural Arrhythmic Focus.

BACKGROUND: Conventional mapping of focal ventricular arrhythmias relies on unipolar electrogram characteristics and early local activation times. Deep intramural foci are common and associated with high recurrence rates following catheter-based radiofrequency ablation. We assessed the accuracy of unipolar morphological patterns and mapping surface indices to predict the site and depth of ventricular arrhythmogenic focal sources. METHODS: An experimental beating-heart model used Langendorff-perfused, healthy swine hearts. A custom 56-pole electrode array catheter was positioned on the left ventricle. A plunge needle was placed perpendicular in the center of the grid to simulate arrhythmic foci at variable depths. Unipolar electrograms and local activation times were generated. Simulation models from 2 human hearts were also included with grids positioned simultaneously on the endocardium-epicardium from multiple left ventricular, septal, and outflow tract sites. RESULTS: A unipolar Q or QS complex lacks specificity for superficial arrhythmic foci, as this morphology pattern occupies a large surface area and is the predominant pattern as intramural depth increases without developing a R component. There is progressive displacement from the arrhythmic focus to the surface exit as intramural focus depth increases. A shorter total activation time over the overlying electrode array, larger surface area within initial 20 ms activation, and a dual surface breakout pattern all indicate a deep focus. CONCLUSIONS: Displacement from the focal intramural origin to the exit site on the mapping surface could lead to erroneous lesion delivery strategies. Traditional unipolar electrogram features lack specificity to predict the intramural arrhythmic source; however, novel endocardial-epicardial mapping surface indices can be used to determine the depth of arrhythmic foci.

Detailed Assessment of Low-Voltage Zones Localization by Cardiac MRI in Patients With Implantable Devices.

OBJECTIVES: The purpose of this study was to assess the performance and limitations of low-voltage zones (LVZ) localization by optimized late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) scar imaging in patients with cardiac implantable electronic devices (CIEDs). BACKGROUND: Scar evaluation by LGE-CMR can assist ventricular tachycardia (VT) ablation, but challenges with electroanatomical maps coregistration and presence of imaging artefacts from CIED limit accuracy. METHODS: A total of 10 patients underwent VT ablation and preprocedural LGE-CMR using wideband imaging. Scar was segmented from CMR pixel signal intensity maps using commercial software (ADAS-VT, Galgo Medical) with bespoke tools and compared with detailed electroanatomical maps (CARTO). Coregistration of EP and imaging-derived scar was performed using the aorta as a fiducial marker, and the impact of coregistration was determined by assessing intraobserver/interobserver variability and using computer simulations. Spatial smoothing was applied to assess correlation at different spatial resolutions and to reduce noise. RESULTS: Pixel signal intensity maps localized low-voltage zones (V <1.5 mV) with area under the receiver-operating characteristic curve: 0.82 (interquartile range [IQR]: 0.76-0.83), sensitivity 74% (IQR: 71%-77%), and specificity 78% (IQR: 73%-83%) and correlated with bipolar voltage (r = -0.57 [IQR: -0.68 to -0.42]) across patients. In simulations, small random shifts and rotations worsened LVZ localization in at least some cases. The use of the full aortic geometry ensured high reproducibility of LVZ localization (r >0.86 for area under the receiver-operating characteristic curve). Spatial smoothing improved localization of LVZ. Results for LVZ with V <0.5 mV were similar. CONCLUSIONS: In patients with CIEDs, novel wideband CMR sequences and personalized coregistration strategies can localize LVZ with good accuracy and may assist VT ablation procedures.

Intramural mapping of intramural septal ventricular arrhythmias.

BACKGROUND: Intramural ventricular arrhythmias (VAs) can originate in patients with or without structural heart disease. Electrogram (EGM) recordings from intramural sources of VA have not been described thoroughly. OBJECTIVE: We hypothesized that the presence of scar may be linked to the site of origin (SOO) of focal, intramural VAs. METHODS: In a series of 21 patients (age: 55 ± 11 years, 12 women, mean ejection fraction 43 ± 14%) in whom the SOO of intramural VAs was identified, we analyzed bipolar EGM characteristics at the SOO and compared the findings with the endocardial breakout site. The patients were from a pool of 86 patients with intramural VAs referred for ablation. RESULTS: In 16/21 patients intramural scarring was detected by cardiac magnetic resonance (CMR) imaging In patients in whom the intramural SOO was reached, intramural bipolar EGMs showed a lower voltage and had broader EGMs compared to the endocardial breakout sites (0.97 ± 0.56 vs. 2.28 ± 0.15 mV, p = .001; and 122.3 ± 31.6 vs. 96.5 ± 26.3 ms, p < .01). All intramural sampled sites at the SOO had either low voltage or broad abnormal EGMs. The activation time was significantly earlier at the intramural SOO than at breakout sites (-36.2 ± 11.8 vs. -23.2 ± 9.1 ms, p < .0001). CONCLUSIONS: Sites of origin of intramural VAs with scar by CMR display EGM characteristics of scarring, supporting that scar tissue localizes to the SOO of intramural outflow tract arrhythmias in some patients. Scarring identified by CMR may be helpful in planning ablation procedures in patients with suspected intramural VAs.

Rotational Activation Pattern During Functional Substrate Mapping: Novel Target for Catheter Ablation of Scar-Related Ventricular Tachycardia.

BACKGROUND: Recent advancements in a 3-dimensional mapping system allow for the assessment of detailed conduction properties during sinus rhythm and thus the establishment of a strategy targeting functionally abnormal regions in scar-related ventricular tachycardia (VT). We hypothesized that a rotational activation pattern (RAP) observed in maps during baseline rhythm was associated with the critical location of VT. METHODS: We retrospectively examined the pattern of wavefront propagation during sinus rhythm in patients with scar-related VT. The prevalence and features of the RAP on critical VT circuits were analyzed. RAP was defined as >90° of inward curvature directly above or at the edge of the slow conductive areas. RESULTS: Forty-five VTs in 37 patients (66±15 years old, 89% male, 27% ischemic heart disease) were evaluated. High-density substrate mapping during sinus rhythm (median, 2524 points) was performed using the CARTO3 system before VT induction. Critical sites for reentry were identified by direct termination by radiofrequency catheter ablation in 21 VTs or by pace mapping in 12 VTs. Among them, RAP was present in 70% of the 33 VTs. Four VTs had no RAP at the critical sites during sinus rhythm, but it became visible in the mappings with different wavefront directions. Six VTs, in which intramural or epicardial isthmus was suspected, were rendered noninducible by radiofrequency catheter ablation to the endocardial surface without RAP. RAP had a sensitivity and specificity of 70% and 89%, respectively, for predicting the elements in the critical zone for VT. CONCLUSIONS: The critical zone of VT appears to correspond to an area characterized by the RAP with slow conduction during sinus rhythm, which facilitates targeting areas specific for reentry. However, this may not be applicable to intramural VT substrates and might be affected by the direction of wavefront propagation to the scar during mapping. Graphic Abstract: A graphic abstract is available for this article.

Ventricular arrhythmias in mouse models of diabetic kidney disease.

Chronic kidney disease (CKD) affects more than 20 million people in the US, and it is associated with a significantly increased risk of sudden cardiac death (SCD). Despite the significance, the mechanistic relationship between SCD and CKD is not clear and there are few effective therapies. Using optical mapping techniques, we tested the hypothesis that mouse models of progressive diabetic kidney disease (DKD) exhibit enhanced ventricular arrhythmia incidence and underlying arrhythmia substrates. Compared to wild-type mice, both Leprdb/db eNOS-/- (2KO) and high fat diet plus low dose streptozotocin (HFD + STZ) mouse models of DKD experienced sudden death and greater arrhythmia inducibility, which was more common with isoproterenol than programmed electrical stimulation. 2KO mice demonstrated slowed conduction velocity, prolonged action potential duration (APD), and myocardial fibrosis; both 2KO and HFD + STZ mice exhibited arrhythmias and calcium dysregulation with isoproterenol challenge. Finally, circulating concentrations of the uremic toxin asymmetric dimethylarginine (ADMA) were elevated in 2KO mice. Incubation of human cardiac myocytes with ADMA prolonged APD, as also observed in 2KO mice hearts ex vivo. The present study elucidates an arrhythmia-associated mechanism of sudden death associated with DKD, which may lead to more effective treatments in the vulnerable DKD patient population.

Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: A Translational Perspective for the Clinician-Scientist.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and potentially lethal inherited arrhythmia disease characterized by exercise or emotion-induced bidirectional or polymorphic ventricular tachyarrhythmias. The median age of disease onset is reported to be approximately 10 years of age. The majority of CPVT patients have pathogenic variants in the gene encoding the cardiac ryanodine receptor, or calsequestrin 2. These lead to mishandling of calcium in cardiomyocytes resulting in after-depolarizations, and ventricular arrhythmias. Disease severity is particularly pronounced in younger individuals who usually present with cardiac arrest and arrhythmic syncope. Risk stratification is imprecise and long-term prognosis on therapy is unknown despite decades of research focused on pediatric CPVT populations. The purpose of this review is to summarize contemporary data on pediatric CPVT, highlight knowledge gaps and present future research directions for the clinician-scientist to address.

Novel cases of pediatric sudden cardiac death secondary to TRDN mutations presenting as long QT syndrome at rest and catecholaminergic polymorphic ventricular tachycardia during exercise: The TRDN arrhythmia syndrome.

TRDN mutations cause catecholaminergic polymorphic ventricular tachycardia (CPVT) but may present with abnormal electrocardiogram (ECG) findings provoking a diagnosis of long QT syndrome (LQTS). We report two novel cases of sudden cardiac death in children due to mutations of TRDN, providing further insight into this rare and aggressive inherited arrhythmia syndrome. Whole exome sequencing (WES) was performed in two unrelated children who experienced cardiac arrest during exercise and were negative for targeted testing of LQTS. WES identified a novel homozygous splice-site mutation in both patients, denoted c.22+1G>T, absent from gnomAD and suggesting a founder variant in the Iranian population. We now summarize the genetic architecture of all reported TRDN-related patients, including 27 patients from 21 families. The average age-onset was 30 months (range 1-10) for all cases. Adrenergic-mediated cardiac events were common, occurring in 23 of 27 cases (85%). LQTS was diagnosed in 10 cases (37%), CPVT in 10 (37%) cases, and in 7 cases. No phenotypic diagnosis was provided. Five cases (15%) had evidence for associated skeletal myopathy. Four missense TRDN variants (24%) were observed in diseased cases, while the remaining variants reflect putative loss-of-function (LOF) mutations. No disease phenotype was reported in 26 heterozygous carriers. In conclusion, TRDN mutations cause a rare autosomal recessive arrhythmia syndrome presenting with adrenergic-mediated arrhythmic events, but with ECG abnormalities leading to a diagnosis of LQTS in a proportion of cases. Heterozygous carriers are free of disease manifestations.